Field of the Disclosure
The disclosure relates generally to methods for diagnosing and treating diseases and disorders, and related compositions and kits useful therefor. More particularly, the disclosure relates to methods for diagnosing and treating catabolism-related vitamin D deficiency and susceptibility thereto, related compositions and kits, and methods for preventing and treating related disorders.
Brief Description of Related Technology
Humans acquire vitamin D from dietary sources and from the UV light-dependent conversion of 7-dehydroxcholesterol to vitamin D3. Vitamin D3 (or cholecalciferol) and vitamin D2 (or ergocalciferol) are collectively referred to as “vitamin D” and are fat-soluble precursors to the active vitamin D hormones. Metabolism of vitamin D3 and vitamin D2 occurs primarily in the liver to produce 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2, respectively (collectively referred to herein as “25-hydroxyvitamin D”), which are prohormones of the respective active vitamin D hormones. Further metabolic activation of these vitamin D prohormones occurs mainly in the kidneys by a cytochrome P450 enzyme, CYP27B. CYP27B is also expressed in many extra-renal vitamin D target tissues and can effect local activation of 25-hydroxyvitamin D to produce autocrine and/or paracrine hormonal responses. Specifically, 25-hydroxyvitamin D3 is metabolized to the active hormone 1,25-dihydroxyvitamin D3 (or calcitriol) and 25-hydroxyvitamin D2 is metabolized to the active hormone 1,25-dihydroxyvitamin D2 (collectively referred to herein as “1,25-dihydroxyvitamin D”).
The vitamin D hormones regulate a variety of cellular processes via interactions with vitamin D receptors (VDR). In particular, the vitamin D hormones regulate blood calcium levels by controlling the absorption of dietary calcium by the small intestine and the reabsorption of calcium by the kidneys. Excessive hormone levels can lead to abnormally elevated urine calcium (hypercalciuria), blood calcium (hypercalcemia) and blood phosphorus (hyperphosphatemia). Vitamin D deficiency, on the other hand, is associated with secondary hyperparathyroidism, parathyroid gland hyperplasia, hypocalcemia, chronic kidney disease (CKD), and metabolic bone diseases such as osteitis fibrosa cystica, osteomalacia, rickets, osteoporosis, and extraskeletal calcification. Vitamin D hormone has been reported to have many diverse “non-classical” biologic effects beyond its “classical” effects on the parathyroid hormone system. Such effects have been reported in connection with cellular proliferation, the immune system and the cardiovascular system, including the renin-angiotensin system, blood pressure, cellular growth and differentiation, antifibrosis, red blood cell formation, hair growth, and muscular function.
Catabolism of vitamin D prohormones, hormones, and analogs is accomplished through the action of cytochrome P450 enzymes. The cytochrome P450 enzyme CYP24 catalyzes the first step in the catabolism of various vitamin D compounds. In particular, for example, CYP24 carries out the conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 and the conversion of 1,25-dihydroxyvitamin D3 (calcitriol) to 1,24,25-trihydroxyvitamin D3 eventually giving rise to calcitroic acid. CYP24 can also hydroxylate at the 23 position, resulting in the production of the terminal metabolite 1,25-dihydroxyvitamin D3-26,23-lactone. Further processing by Phase II catabolic enzymes ultimately leads to clearance of vitamin D compounds from the body.